Mild reductive rearrangement of oximes and oxime ethers to secondary amines with hydrosilanes catalyzed by B(C 6 F 5 ) 3 †

The strong boron Lewis acid tris(pentafluorophenyl)borane, B(C 6 F 5 ) 3 , has been found to catalyze the reductive rearrangement of oximes and its ether derivatives at room temperature with hydrosilanes as the reducing agents. Cyclic substrates undergo ring enlargement, and the secondary amine products are generally formed in good yields. Control experiments combined with a DFT computational analysis of the reaction mechanism suggest that there are three energetically accessible reaction pathways (Paths A–C), either or not involving hydroxylamine derivatives. Paths A and B proceed through the intermediacy of a common N , O -bissilylated hydroxylamine, and the ring-expanding rearrangement yields an iminium ion. With no intermediate at the hydroxylamine oxidation level (Path C), the reaction mechanism resembles that of the Beckmann rearrangement where an O -silylated oxime converts into a nitrilium ion. The reduction– rearrangement sequence (Paths A and B) is slightly preferred over the rearrangement–reduction order of events (Path C), especially at ambient temperature. Oximes and its ether derivatives as well as the corresponding hydroxylamines rearrange to secondary amines when reacted with hydrosilanes such as PhSiH 3 with B(C 6 F 5 ) 3 as catalyst. Computations suggest a reduction– rearrangement to be slightly favored over a rearrangement–reduction Beckmann-type sequence.


Introduction
A few years ago, our laboratory disclosed the previously elusive hydrogenation of various oxime ethers to the corresponding Oprotected hydroxylamines by making use of FLP-type dihydrogen activation with B(C 6 F 5 ) 3 as catalyst 1 (Scheme 1, top). 2 The goal of that project had been to avoid the otherwise typical cleavage of the weak N-O bond to afford primary amines. 3 For this, the use of dihydrogen is critical because hydrosilanes as alternative reductants 4 engage in deoxygenation. 5 Treatment of those oxime ethers with hydrosilane/B(C 6 F 5 ) 3 combinations results in exactly that, and these reactions were not clean but there was evidence for a reductive rearrangement. 2a Rearrangements of this sort that convert oximes and its ether derivatives into secondary amines can be achieved by the stoichiometric use of aluminum- 6 and also boron-based 7 reductants; the aforementioned reduction to primary amines is a common side reaction (Scheme 1, bottom). In the light of our earlier observations, we decided to investigate the B(C 6 F 5 ) 3 -catalyzed reductive rearrangement of oximes with hydrosilanes to turn it into a useful chemoselective methodology. Scheme 1 Reduction and reductive rearrangement of oximes and oxime ethers catalyzed by combinations of B(C 6 F 5 ) 3 and dihydrogen and hydrosilanes (n = 1-3), respectively. R 1 and R 2 = aryl, alkyl, and H; R 3 = alkyl or silyl; R 4 = alkyl, silyl, or H.
In toluene-d 8 , excellent and good yields were also obtained with MePhSiH 2 and Ph 2 SiH 2 , respectively (entries 7 and 8). Other hydrosilanes such as Et 2 SiH 2 and Me 2 PhSiH were however completely unreactive even at higher temperature (entries 9 and 10, see the Supporting Information for details). Reactions conducted with shorter reaction time (entry 11), less PhSiH 3 (entry 12), or decreased catalyst loading (entry 13) resulted in lower yields. Incomplete conversion at reduced catalyst loadings could be compensated by longer reaction times. The yield of the above reductive rearrangement was also high on a 7.0 mmol scale, and we continued exploring the reaction scope under this optimized reaction setup (Scheme 2; cf. Table  1, entry 6). Related ring enlargements worked equally well [(E)-1ba,ca → 2b,c]. The functional-group tolerance was assessed with acetophenone-derived oxime derivatives (E)-1da-pa bearing a range of electron-donating and -withdrawing substituents on the aryl group. The four halo groups as in (E)-1ia-la were compatible with the reaction conditions but aryl iodide (E)-1la underwent partial hydrodeiodination to afford 2l in 57% along with 2d in 25% yield. A thioether as in (E)-1na and a free phenol as in (E)-1oa undergoing temporary silylation were tolerated as well. Exhaustive hydrodefluorination of the trifluoromethyl group in (E)-1ma occurred, furnishing 2h rather than 2m. 8 The reaction of (E)-1pa with a dimethylamino group in the para position only gave a trace amount of 2p, and the deamination product 4-ethyl-N,N-dimethylaniline was formed in 64% yield. 9 It is important to note that the configuration of the oxime does not affect the reaction outcome; 6g both (E)-1ka and (Z)-1ka yielded 2k in 98% and 93%, respectively.  We briefly investigated the reductive rearrangement of other alkyl-substituted benzylic oximes (Scheme 2). (E)-1ra and (E)-1sa with a 1° alkyl and a benzylic substituent converted selectively and in high yields into the corresponding secondary amines. However, substrates with 2° and 3° alkyl groups did lead to mixtures of rearranged products because the migrating ability of these groups (out)competes with that of the aryl group. This finding is different from previous reports. 6g The results obtained with isopropyl, cyclohexyl, and tert-butyl are summarized in the Supporting Information. Symmetric ketoximes such as diaryl-substituted 1ta and 1ua as well as dialkyl-substituted 1va-xa reacted cleanly but for the latter a reaction temperature of 120 °C was necessary to achieve high conversion. The rearrangement of unsymmetrically substituted (E/Z)-1ya furnished 2y selectively with migration of the phenethyl group. Additional substrates were subjected to the standard procedure (Scheme 3). Aldoxime (E)-1za rearranged to the aniline derivative 2z in good yield. Moreover, the diamine 5 was obtained from bisoxime (Z,Z)-4 by two-fold rearrangement in moderate yield.
Page 2 of 8 Organic Chemistry Frontiers   1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 → 2a-d 1 ). This suggests that oximes and their congeners are reduced to the hydroxylamine oxidation level during the course of the reaction. 2, 10 Cho, Tokuyama, and co-workers had reported the same for the related DIBAL-Hmediated rearrangement, and their computed mechanism passes through a three-centered transition-state for the concerted aryl migration followed by hydride reduction of the resulting iminium ion 6g (silyliminium ion in the case of hydrosilane/B(C 6 F 5 ) 3 combinations). We then conducted density functional calculations (DFT) to explore the mechanistic details of the reductive rearrangement of oximes to secondary amines. The calculations were performed at M06-2X/cc-pVTZ//M06-2X/6-311G(d,p) level of theory 11 using the Gaussian 16 software, 12 with toluene solvation incorporated via a polarizable continuum model (PCM) at the same level of theory. 13 The reaction between oxime (E)-1aa and PhSiH 3 was chosen as a model system. Optimized geometries and free energy profiles (including the computational analysis on the relative stability of the B(C 6 F 5 ) 3 ·(E)-1aa Lewis pair and the B(C 6 F 5 ) 3 ·hydrosilane η 1adduct I1 14 ) involved in the catalytic cycle are provided in the Supporting Information. 15 As shown in Scheme 7, the reaction begins with the activation of Si-H bond in I1 by the nitrogen atom or oxygen atom in oxime (E)-1aa 16,17 to afford N-silyliminium ion I2 (Path A) or silyloxonium ion I8 (Path B) with the borohydride [HB(C 6 F 5 ) 3 ] − as the counteranion. Our calculations indicate that the corresponding S N 2-Si transition states do not exist in the case of PhSiH 3 . 17,18 Instead, two stable trigonal bipyramidal transition complexes (rather than transition state) were located (I2' or I8', see Figure S70 in the Supporting Information). 19 These results are different from that found in a computational study on B(C 6 F 5 ) 3 -catalyzed carbonyl hydrosilylation with a tertiary silane (Me 3 SiH). 17 20 Finally, I7 further reacts through a barrierless hydride transfer process from the borohydride to the iminium ion to form the reductive rearrangement product 2a-Si (gray box). The overall reaction is exergonic by 98.1 kcal/mol, and both Path A and Path B are likely related to the formation of the reductive rearrangement product because of the close activation barriers in the ratedetermining steps involved (Path A, I6 → I7, ΔG ‡ = 23.5 kcal/mol; Path B, I10 → I5, ΔG ‡ = 24.1 kcal/mol). These computational results can account for the experimental observation that oxime ethers and several hydroxylamine derivatives are also applicable to this method.
We also considered the possibility of the classical Beckmann rearrangement 21 (Path C, see Figures S68 and S69 in the Supporting Information for details). This pathway proceeds through the reaction of I9 with the B(C 6 F 5 ) 3 ·hydrosilane adduct I1 to form the bissilyloxonium ion I11 with the oxygen atom as the nucleophilic center. Aryl migration and N-O bond cleavage of I11 further leads to the formation of ternary complex I12, in which both the borohydride and the disiloxane are loosely bound to the carbon atom of the nitrilium ion (see Figure S69 for the structural details of I12). Subsequent hydride reduction accompanied by disiloxane displacement yields the ringexpanded imine I13 along with B(C 6 F 5 ) 3 . A subsequent imine hydrosilylation 10 through N-silyliminium ion I14 furnishes the reductive rearrangement product 2a-Si (gray box) The ratedetermining step of this pathway is the aryl migration/N-O bond cleavage in intermediate I11 with an activation barrier of 25.7 kcal/mol. Although this process is kinetically less favorable than Paths A or B, we cannot exclude whether this pathway contributes to the formation of the related reductive rearrangement product, especially in cases where higher reaction temperatures are applied. The direct hydride transfer from the borohydride to the nitrogen atom of intermediate I6 or I11 to eventually form the primary amine 3a is kinetically disfavoured (cf. gray box in Table  1). The corresponding barriers are estimated to be at least 65.9 and 47.6 kcal/mol, respectively (relative to separated reactants; see Figures

Conclusion
In summary, we have developed an effective catalytic reductive rearrangement of oximes and its congeners to selectively give secondary amines. Aryl-substituted secondary and primary hydrosilanes work as stoichiometric reductants, and catalyst loadings of 10 or 2.5 mol% of B(C 6 F 5 ) 3 are sufficient to secure synthetically useful yields. Quantum-chemical calculations revealed that this reductive rearrangement can follow two distinct order of events (Scheme 7): reduction-rearrangement involving hydroxylamine derivatives (Paths A and B) or rearrangement-reduction (Path C). The ring expansion yields an iminium ion (Paths A and B) or a nitrilium ion (Path C). All pathways are energetically accessible but Paths A and B are kinetically favored at room temperature; Path C becomes competitive in those cases where high reaction temperatures are required. Hence, a Beckmann rearrangement (Path C) cannot be excluded but reduction followed by ring-expanding migration is more likely. The method indeed extends to hydroxylamine derivatives which is in agreement with the computed mechanism and control experiments. The new protocol avoids the previously used stoichiometric aluminumand boron-based reductants.